Targeting Monoamine Oxidases with Multipotent Ligands: An Emerging Strategy in the Search of New Drugs Against Neurodegenerative Diseases

L.      Pisani; M.      Catto; F.      Leonetti; O.      Nicolotti; A.      Stefanachi; F.      Campagna; A.      Carotti

Abstract

The socioeconomic burden of multi-factorial pathologies, such as neurodegenerative diseases (NDs), is enormous worldwide. Unfortunately, no proven disease-modifying therapy is available yet and in most cases (e.g., Alzheimer's and Parkinson's disease) the approved drugs exert only palliative and symptomatic effects. Nowadays, an emerging strategy for the discovery of disease-modifying drugs is based on the multi-target directed ligand (MTDL) design, an innovative shift from the traditional approach one-drug-one-target to the more ambitious one-drug-more-targets goal. Herein, we review the discovery strategy, the mechanism of action and the biopharmacological evaluation of multipotent ligands exhibiting monoamine oxidase (MAO) inhibition as the core activity with a potential for the treatment of NDs. In particular, MAO inhibitors exhibiting additional acetylcholinesterase (AChE) or nitric oxide synthase (NOS) inhibition, or ion chelation/antioxidant-radical scavenging/anti-inflammatory/A2A receptor antagonist/APP processing modulating activities have been thoroughly examined.

Keywords: Multi-target directed ligands, Monoamine oxidase inhibition, Acetylcholinesterase inhibition, Neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, socioeconomic burden, multi-factorial pathologies, ND, MTDL